DD280109A1 - PROCESS FOR PREPARING SUBSTITUTED 1,2,4-TRIAZOLO / 1.5-A / PYRIDINES - Google Patents

Abstract

The invention relates to a process for preparing substituted 1,2,4-triazolo & 1,5-a! Pyridine, which can be used in principle in the therapy of cardiovascular diseases due to their positive inotropic activity. According to the invention, 2-imino-2H-pyridin-1-amines are reacted with carboxylic anhydrides, orthocarboxylic acid derivatives or O-alkylated carboxylic acid amides to give substituted 1,2,4-triazolo & 1,5-a! Pyridines of the general formula I. The invention can be used in the chemical and pharmaceutical industries. Formula I

Description

Characteristic of the known state of the art

It is known that 8-cyano-1,3,4-oxadiazolo [3.2-a | pyridinium salts with cyanamide to 2-amino-1,2,4-triazolo [1.5-a | Boyd, SR Dando: J. Chem. Soc., C3873 (1971)). The method has the disadvantage that it is not unsubstituted in the 2-position and no 2-alkyl and 2-aryl It is also known that N- [3- (1,2,4-oxadiazol-3-yl) -pyrid-2-yl] -formamidoxirnm »hermisch to 1.2 B.4-tiazolo [1.5-al-pyridine-8-carbonitrile can be cyclized (B.Vercek, B.Stanovnik, M.Tisler: J. Org Chem 44, 1965 [19791].) This process requires the use of a starting compound which is difficult to access Furthermore, it is known that 3-cyanopyridine-i-imines react with nitriles to form 2-alkyl-1,2,4-triazolo [1 .Sa]. Python-8-carbonitriles (PJ West, JH Parsons: British Patent 1,574,415, Chem. Abstr 93,46730 m (198O)). Besides the fact that only low yields are achieved with the aid of this process, acts si ch a required reaction time of several days from particularly disadvantageous. In addition, it is known that 2-alkyl-1,2,4-triazolo (1 .5-a] pyridine-8-carbonitriles by oxidative ring closure of N- (3-cyanopyrid-2-yl) substituted amidines and by base-catalyzed isomerization of 3 Alkyl-1,2,4-triazolo (4.3-a-pyridine-8-carbonitriles) can be prepared (PJWest, JH Parsons: Brit. Pat. 1.574.415, Chem. Abstr. 93.46730 m (19801). Both processes have the disadvantage that they require the use of starting compounds which are difficult to prepare.Also, it is known that 1-amino-3-cyanopyrid-2-ones with carboxylic acid amides are 1,2,4-triazolo (1,5-a] pyridine-8-carbonitriles RC Phadke, DW Rangnekar: Synthesis 860 (19861) A disadvantage of this process is the long reaction times and the fact that no unsubstituted 5-position substituents can be prepared by this method.

Furthermore, it is known that compounds having a 1,2-diaminopyridine structure react with carboxylic acid derivatives to give 1,2,4-triazolo [1,5-alpiridines (KT Potts, HR Burton, J. Bhattacharyya: J. Org. Chem. 31,260 (19661; T. Okamoto, M. Hirobe, Y. Tamai, E. Yabe: Chem. Pharm. Bull. 14, 506 [1966]; C. Casagrande, A. lnvetnizzi: Farmaco, Ed., P. 27, 101 (1972), Chem. Abstr., 76, 126683 (1972); K.Kdbo, N.ltoh, I.Sohzu, Y. solomura, H.Honma: Jap. Pat., 79.05.996, Chem. Abstr. 91, 57007, [1979]; Suzue: Jap. Pat., 79.39.094, Chem. Abstr 91,91646 (19791; T. Lrikura, S. Suzuue: US Pat. 4,202,977, Chem. Ab. * Tr. 94, 4021 w [1981]; T Irikura, S. Suzuue: DE-OS 2,905,823, Chem. Abstr. 94, 121541 b (1981); Kanebo Ltd: Jap. Pat. 81.63.983, Chem. Abstr. 95, 203964 b [1981]; Kyorin Pharmaceutical Co., Ltd .: Franz Pat., 2,450,259, Chem. Abstr., 97, 73773 (1982), A. McKloplop, A. Henderson, PS Ray, C. Avendano, EG Molinero: Tetrahedron Letters 23,3357 [1982]; Kyorin Pharmaceutical Co., Ltd .: Jap. Pat. 82 .206,684, Chem. Abstr. 98.160725 s [1983]).

It is further known that semicyclic amidrazones react with orthocarboxylic acid esters to form fused 1,2,4-triazoles (H.Reimlinger, JM Vandewalle, WRF Lingier: Chem. Ber. 103, 1960 [19701, M. Kocevar, S. Polanc, B Stanovnik, F. Skerjanc, M. Tisler: Bull. Chem. Soc. Jpn 55,349 [1982]; DB Moran, DW Powell, JD Albright: US Pat. 4,550,166, Chem. Abstr. 104, 1299111 (1986) J. Svetlik: Heterocycles 24, 1619 [1986]).

In addition, it is known that 1,2,4-triazolo [1,5-a] pyridines have both antiviral (H. Berner, H. Reinshagen: Monatsh. Chem. 106, 1059 [1975]) and analgesic, antipyretic, antiphlogistic (K. Kubo , N.ltoh, I.Sohzu, Y. solomura, H.Honma: Jap. Pat. 79.05.966, Chem. Abstr. 91, 57007 (1979) and in particular antihypertensive (S. Suzuue: Jap. Pat. 79.39. 094, Chem. Abstr. 91,91646 [1979]; T.lrikura, S. Suzuue: US Pat. 4,202,977. Chem. Abstr 94,4021 w [1981]; T.lrikura, S. Suzuue: DE Chem. Abstr 94, 121541 b [1981]; Kyotin Pharmaceutical Co., Ltd .: Franz. Pat. 2,450,259, Chem. Abstr. 97,72373 ζ [1C82]; Kyorin Pharmaceutical Co., Ltd .; : Jap. Pat. 82,206,684, Chem. Abstr. 98, 160725 (19831).

Object of the invention

The aim of the invention is to provide an economically advantageous, synthetically simple and readily available starting compounds based method for preparing substituted 1,2,4-triazolo | 1.5-alpyridine, which are unsubstituted in the 5-position and in the 8-position possess a nitrile group and the Treatment of cardiovascular disease.

Explanation of the essence of the invention

The object of the invention is to develop a process for preparing substituted 1,2,4-triazolo [1,5-a] pyridines which are unsubstituted in the 5-position and have a nitrile group in the 8-position, starting from readily available starting compounds requires as short reaction times and only one process stage and allows to isolate the final products without complex separation operations

 According to the invention, this object is achieved in that substituted 1,2,4-triazolo [1.5-a | pyridine of the general formula I,

in the R and R ^{1 are} identical or different hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl or RR ¹ together a tri-, tetra-, penta, hexa or decamethylene bridge or a benzo-fused alkenylene bridge and R ^{2 is} hydrogen, alkyl or aryl, are prepared by reacting a 2-imino-2H-pyridin-1-amine of the general formula II

CN

with the meaning given for R and R 'or RR ¹ with a carboxylic anhydride of the general formula III, (R ² -CO) ₂ O III

in which R ^{2 is} alkyl or aryl, in an organic solvent or in an excess of the carboxylic anhydride of general formula III or in a weak acid as solvent or in an organic solvent in the presence of a weak acid, or with a carboxylic anhydride of general formula IV,

rJ-CO-O-CO-R ³ IV

in which R ^{2 is} hydrogen and R ^{3 is} alkyl, in an organic solvent or in an excess of the carboxylic anhydride of the general formula IV or in a weak acid as solvent or in an organic solvent in the presence of a weak acid, or with an orthocarboxylic acid derivative of the general formula V

R ² C (OAlkyl) _n (NR ⁴ R ⁵ ) ₃ "V

with the explanation given for R ² and in which R ⁴ and R ^{5 are} identical or different alkyl or NR ⁴ R ⁵ together pyrrolidin-1-yl, piperidino or morpholine) and η is 0,1, 2 or 3, in an organic solvent or in an excess of the orthocarboxylic acid derivative of the general formula V or in a weak acid as a solvent, or with an O-alkylated carboxamide of the general formula VI

R ² C (OAlkyl) (NR ⁴ R ⁵ rx ~ Vl

with the explanation given for H ² , R ⁴ and R ⁵ or NR ⁴ R ⁵ and in which X "denotes an alkyl sulfate or tetrafluoroborate anion, in an organic solvent in the presence of a strong base As an organic solvent, an aliphatic alcohol, such as For example, methanol, ethanol, iso-propanol or n-butanol, or acetonitrile or an N-N-disubstituted carboxylic acid amide such as dimethylformamide or dimethylacetamide is used as the weak acid, an aliphatic carboxylic acid such as acetic acid or propionic acid, or orthophosphoric acid or phosphorous Acid or p-toluenesulfonic acid is used. As the strong base, an alkali metal alcoholate such as sodium methylate or sodium ethylate is used.

The teaching according to the invention makes it possible to make the substituted 1,2,4-triazolo [1,5-alxyridines of the general formula I in a simple manner, accessible in short reaction times in only one process step and without complex separation operation, using easily prepared starting material bonds. The products of general formula I according to the invention are new. Surprisingly, they have a positive inotropic activity, which was not to be expected according to the prior art. Thereafter, of 1,2,4-triazolo [1.5-a] pyridines with respect to the cardiovascular system only their antihypertensive efficacy known.

Execution examples

example 1

The substituted 1,2,4-triazolo (1,5-a) pyridines of the general formula I! Prepared according to the various variants are summarized in Table 1.

Variant A 10 ml of formic acid / acetic anhydride are added, with stirring, to 10 mmol of 2-imino-2H-pyridin-1-amine of the general formula II in small portions, the mixture being vigorously heated. After cooling, the reaction solution is diluted with 20 ml of water. The precipitated end product of general formula I (R ² = H) is filtered off, washed with water and ethanol, dried in air and recrystallized.

Variant B To a solution of 10 mmol of 2-imino-2H-pyridin-1-amine of the general formula II in 10 ml of acetic acid is added 15 mmol of acetic anhydride and the mixture is refluxed for 1 hour. After cooling, the reaction solution is diluted with 20 ml of water. The precipitated end product of general formula I (R ² = CHa) is isolated and purified as described for A.

Variant C To a solution of 10 mmol of 2-imino-2H-pyrid'n-1-amine of the general formula Hin 25 ml of acetonitrile are added 1 mmol of p-Toluensuifcnsäure and 15 mmol of benzoic anhydride and the mixture is refluxed for 2 hours. After cooling, the reaction solution is diluted with 50 ml of water. The precipitate is filtered off, washed with water and to remove the by-produced benzoic acid with 25m! 1 η sodium hydroxide solution treated. The remaining as residue end product of the general formula I (R ² = C ₆ H ₅ ) is filtered off, washed with water until neutral, dried in air and recrystallized.

Variant D Analogous to B, but 15 mmol Triethylorthoformiat be used instead of acetic anhydride. The precipitated end product of general formula I (R ² = H) is isolated and purified as described for A.

Variant E Analogous to D, but instead of triethyl orthoformate 15 mmol of trimethyl orthoformate are used.

Variant F Analogous to D, but instead of acetic acid, 10 ml of propionic acid are used as solvent.

Variant G To a solution of 10 mmol of 2-imino-2H-pyridin-1-amine of the general formula II in 25 ml of acetonitrile is added 1 mmol of 85% orthophosphoric acid and 15 mmol of triethyl orthoformate and the mixture is refluxed for 1 hour. After cooling, the reaction solution is diluted with 50 ml of water. The precipitated end product of general formula I (R ² = H) is isolated and purified as described for A.

Variant H Analogous to G, but instead of orthophosphoric acid 1 mmol of p-toluenesulfonic acid is used.

Variant I Analogous to B, but 15 mmol of triethyl orthoacetate are used instead of acetic anhydride.

Variant J Analogous to B, but instead of acetic anhydride 15 mmol Triethylonhoben ^ oat are used. The precipitated end product of general formula I (R ² = C _f H ₅ ) is isolated and purified as described for A.

Variant K 15 mmol of dimethylformamide dimethyl acetal are added to a suspension of 10 mmol of 2-imino-2H-pyridin-1-amine of the general formula II in 10 ml of dry methanol. The warming mixture is then stirred for 30 minutes and then diluted with 20 ml of water. The precipitated end product of general formula I (R ² = H) is isolated and purified as described for A.

Variant L Analogously to K, but instead of dimethylformamide dimethyl acetal and methanol, 15 mmol dimethylformamide diethyl acetal and 10 ml dry ethanol are used.

Variant M Analogous to K, but instead of dimethylformamide dimethyl acetal and methanol, 15 mmol of 1-dimethoxymethylpyrrolidine and 10 ml of dry isopropanol are used.

Variant N Analogously to K, however, 15 mmol of 1-dimethoxymethylpiperidine are used instead of dimethylformamide dimethyl acetal.

Variant O Analogous to K, however, 15 mmol of 4-dimethoxymethylmorpholine are used instead of dimethylformamide dimethyl acetal.

Variant P Analogous to K, however, instead of dimethylformamide dimethyl acetal and methanol, 15 mmol of dimethylacetamide diethyl acetal and 10 ml of dry ethanol are used. The precipitated end product of general formula I (R ² = CH ₃ ) is isolated and purified as described for A.

Variant Q Analogous to K, but instead of Dimethylfcrmamiddimethylacetal 15mmol bis (dimethylamino) methoxymethan be used.

Variant R Analogous to K, but instead of Dime.'hylformamiddimethylacetal 15mmol tris (morpholino) methane are used.

Variant S TO a solution of 10 mmol of 2-imino-2H-pyridin-1-amine of the general formula II and 15 mmol of dimethylformamide · dimethyl sulfate adduct in 30 ml of dry methanol is allowed to drop with stirring and exclusion of moisture at room temperature 15 mmol of a freshly prepared methanolic Natriummethylatlösung. After completion of the addition, the mixture is refluxed for 10 minutes. After cooling, the reaction solution is diluted with 50 ml of water. The precipitated end product of the general formula I ( ² = H) is isolated and purified as described for A.

Example 2

The testing of the substituted 1,2,4-triazolo [1.5-a | Pyridine of the general formula I on positive inotropic activity was carried out according to the following method:

The experiments were carried out on anesthetized beagle dogs (2 mg / kg morphine i.m. as premedication, 30 mg / kg pentobarbital i.v., 0.02 mg (kg / min phenobarbital sodium i.v. as continuous infusion) of both sexes of the VEB Jenapha-rn breed.

The test substances were dissolved in propylene glycol and applied in a volume of 0.1 ml / kg in increasing dosages at intervals of 10 minutes by means of a Flexüle in the vena saphena döxtra. A tip catheter (W 121, VEB Meßgerätewerk Zwönitz) was introduced into the left ventricle via the femoral artery of the abdomen for intraventricular pressure measurement. As a measure of the positive inotropic effect, the percentage increase in the maximum rate of pressure rise in the left ventricle (dp / dt _m "in Torr / s) was used.

The measured values for a compound of the general formula i are summarized in Table 2 and compared with amrinone as a reference substance.

Table 1 Prepared substituted 1,2,4-triazolo [1.5-a] pyridhs of the general formula I.

R - (CHj) ₃ - ₆ H ₅ I * - * R ¹ R ² Ausb./% F./°C No. CH ₃ I = CH-CH = C- (CH ₂ ) ₂ - H H variant Recryst. la - (CHj) ₃ - C ₆ H ₅ C4 / A 201 H = CH-C! -L = C- (CH ₂ ) ₂ - 81 / D n-butanol - (CHj) ₃ - C ₆ H ₅ 76 / E 72 / F - (CHj) ₄ - C ₆ H ₅ 61 / G 67 / H - (CH ₂ I ₅ - 74 / K 69 / L H = CH-CH = C-CH ₂ - 56 / M I 52 / N 33/0 -C = CH-CH = CH-CH = C- (CH ₀ ) o- 79 / Q ; 75 / R CH ₃ -C = CH-Cl I H CH ₃ 48 / S ib 54 / B 212.5 to 214 -C = CH-C! 77/1 n-butanol CH ₃ I H C ₆ H ₅ 94 / P ic 63 / C 252-254 C ₂ H ₅ CH ₃ C ₆ H ₅ 12 / J acetic acid ld 34 / J 198 to 199.5 H n-Butnnol le 88 / D 151-152 CH ₃ n-butanol If 61/1 159-160 C ₆ H ₅ n-butanol ig 44 / J 234 to 236.5 H n-butanol lh 88 / D 165.5 to 166.5 H n-butanol ii 85 / D 150 to 151.5 -C = CH-C H n-butanol ii I 90 / D 279-287 (Zers.) K acetic anhydride 97 / D 200-202 Ik CH ₃ nitroethane 92/1 228-229 Il C ₆ H ₅ acetic acid 56 / J 211-214 in the H H acetic acid 95 / D 230-231 In H CH ₃ acetic acid 48/1 161-163 io H C ₆ H ₅ n-butanol 13 / J 246.5 to 249 'P CH ₃ H acetic anhydride 80 / D 184 to 184.5 iq n-butanol

Table 1 (conclusion)

F. Ausb./% / ⁰ C

No. RR ¹ R ² Variant Umkrist.

Ir Fu! -2-yl

Is fur-2-yl

It Fur-2-yl

Thu-2-yl

TABLE 2 Percent change in herpetic tractility (dp / dt ", _ax ) on Beagie dogs' r = 2) after iv bolus application of a compound of general formula I in comparison with amrinone

H H 89 / D 266-267 acetic acid H CH ₃ 70/1 219 to 220.5 n-butanol H C ₆ H ₅ 13 / J 234 to 236.5 acetic acid H H 80 / D 249.5 to 250 acetic acid

amrinone Compound Ie x ± s x ± s Ausgangswerie 2600 ± 1100 3100 ± 900 (Torr / s) dose x% ± s x% ± s (• ng / kg) 0.5 27 ± 13 12 ± 9 1.0 45 ± 13 12 ± 13 2.0 66 ± 25 32 ± 45

η number of animals

x ± s = mean with standard deviation

x ± s = Percent change to baseline with standard deviation

Claims (4)

1. A process for the preparation of substituted 1,2,4-triazolo [1,5-a] pyridines of the general formula I, Chi in the R and R ^{1 are} identical or different hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl or RR ¹ together a tri-, tetra-, penta-, hexa- or decamethylene bridge or a benzo-fused alkenyl bridge and R ^{2 is} hydrogen, alkyl or aryl, characterized in that a 2-imino-2H-pyridin-1-amine of the general formula! II with the meaning given for R and R ¹ or RR ¹ with a carboxylic anhydride of the general formula III, (R ² -CO) ₂ O III in which R ^{2 is} alkyl or aryl, in an organic solvent or in an excess of the carboxylic anhydride of the general formula III or in a weak acid as solvent or in an organic solvent in the presence of a weak acid, or with a carboxylic anhydride of the general formula IV, R ² -CO-O-CO-R ³ IV in which R ^{2 is} hydrogen and R ^{3 is} alkyl, in an organic solvent or in an excess of the carboxylic acid anhydride of the general formula IV or in a weak acid as solvent or in an organic solvent in the presence of a weak acid, or with an orthocarboxylic acid derivative of the general formula V R ² C (OAIkyl) _n (NR ⁴ R ⁵⁾ _{n 3} _ V with the explanation given for R ² and in R ⁴ and R ^{5 are} identical or different alkyl or NR ⁴ R ⁵ together pyrrolidin-1-yl, piperidino or morpholino and η 0,1, 2 or mean, in an organic solvent or in an excess of the orthocarboxylic acid derivative of the general formula V or in a weak acid as solvent, or with an O-alkylated carboxylic acid amide of the general formula VI R ² C (OAlkyl) (NR ⁴ R ⁵ rXVl with the explanation given for R ² , R ⁴ and R ⁵ or NR ⁴ R ⁵ and in which X - is an alkyl sulfate or tetrafluoroborate anion, is reacted in an organic solvent in the presence of a strong base. 2. The method according to claim 1, characterized in that the organic solvent used is an aliphatic alcohol, such as methanol, ethanol, isopropanol or n-butanol, or acetonitrile or an NN-disubstituted carboxylic acid amide, such as dimethylformamide or dimethylacetamide becomes. 3. The method according to claim 1, characterized in that as the weak acid, an aliphatic carboxylic acid, such as acetic acid or propionic acid, or orthophosphoric acid or phosphorous acid or p-toluenesulfonic acid is used. 4. The method according to claim 1, characterized in that as the strong base, an alkali metal such as sodium methoxide or sodium, is used. Field of application of the invention The invention relates to a process for preparing substituted 1,2,4-triazolo (1,5-a-pyridines) Such compounds have a positive inotropic activity and are therefore suitable in principle for use in the therapy of cardiovascular diseases.